The bronchiolar epithelium is an important first line of defense against inhaled environmental stimuli, including microbial products such as CpGcontaining unmethylated DNA. The hypothesis to be tested in this proposal is whether CpG DNA induces signal transduction culminating in activation of the transcription factor NF-kappaB. It is proposed that the pattern recognition receptor (PRR) Toll Like Receptor (TLR)9 is expressed by bronchiolar epithelial cells and initiates signaling induced by CpG DNA. It will be examined whether expression and activity of the NF-kappaB-regulated polymeric immunoglobulin receptor (pIR), essential for the transport of IgA and IgM from the basal to the apical surface of bronchiolar epithelial cells, is augmented by CpG DNA. Finally, the modulation of these pathways in bronchiolar epithelium by CpG DNA may be therapeutically exploited to afford mucosal protection through the augmentation of secretary immunoglobulin levels. The hypothesis will be tested as follows: Specific aim 1) Demonstrate that unmethylated immunostimulatory CpG-containing DNA sequences (CpG DNA) induce signaling events culminating in NF-kappaB activation by bronchiolar epithelial cells. Specific aim 2) Demonstrate that signaling events involving NF-kappaB activation modulate the inducible expression of the polymeric immunoglobulin receptor (plgr) in bronchiolar epithelial cells exposed to CpG DNA. Specific aim 3) Demonstrate that Toll Like Receptor 9 (TLR9) mediates the activation of NF-kappaB and mRNA expression of pIgR in bronchiolar epithelial cells by CpG DNA. Specific aim 4) Demonstrate that intranasal CpG DNA administration augments secretary immunoglobulin levels in the airway through TLR9-mediated NF-kB activation by bronchiolar epithelial cells.